ÓRgÃO OFICIAL DA SOCIEDADE PORTUgUESA DE REUMATOLOgIA
101 EDITORIAL
ACTA REUMATOL PORT. 2016;41:101-103
Investigator iniciated trials in Portuguese rheumatology
Elsa Vieira-Sousa1,2, Alexandre Sepriano3,4, Fernando Pimentel-Santos3,4
a Investigação Clínica) and the experimental drug (IN-FARMED) should be required for the trials including IIS. Clinical trials testing medical devices follow the same rules as medications, with some particularities depending upon the type of trial and device’s specifici-ties1.
To conduct IIS, cooperation among several stake-holders2 is necessary, which represents an organiza-tional effort for clinical investigators, hospitals, academia, research sponsors, patients, physicians, and regulator. Each stakeholder offers a different set of tools to support the essential components of a clinical trial. In fact, Clinical Investigation Centres based at Hospi-tals, can be of help to the investigators to develop and implement clinical trials. Furthermore, academic insti-tutions either Universities or research Institutes have facilities such as biostatistics, legal support and com-munication offices. Pharmaceutical industry is a fun-damental partner for the success of an IIS, through the promotion of research grants and a know-how for con-ducting RCTs. Together, these stakeholders create the infrastructure that supports clinical research.
The Portuguese Rheumatology Society (SPR) has re-cently supported 3 IIS in distinct areas: the GO-DACT, the biomarkers in AS and ViscoOA.
GO-DACT is a nationwide multicentre, interven-tional, double-blinded, placebo-controlled, parallel de-sign trial of golimumab in combination with MTX ver-sus MTX monotherapy, in MTX-naïve psoriatic arthri-tis patients with active dactyliarthri-tis. This trail aims to demonstrate differences of efficacy of golimumab in combination with MTX in comparison with MTX monotherapy, in improving dactylitis at 24 weeks ver-sus baseline, in MTX-naïve PsA patients. GO-DACT In-cludes patients older than 18 years, with the diagnosis of psoriatic arthritis according to the CASPAR criteria3, and ≥1 tender dactylitis, refractory to at least two sys-temic NSAIDs, at optimal dosage, for 3 months. Each subject will participate in the trial for a maximum of appro ximately 32 weeks from the time the subject signs the Informed Consent Form (ICF) through the final contact. After a screening phase of approximately 28 Randomized controlled clinical trials (RCTs) are
con-sidered the highest level of evidence in human experi-mental medicine. Usually designed to assess the effica-cy and safety of new therapies or treatment strategies, that ultimate led to its approval and application in cli -nical practice; they are, in the majority of cases, funded and conducted by a pharmaceutical company. Investigator initiated trials (IIS) are often a unique way to ans -wer particularly relevant questions to clinical practice. They complement available safety and efficacy infor-mation and sometimes the mechanism of action, of a specific therapy. While searching at clinicaltrials.gov, 835 IIS can be identified from a total of more than 200,000 registered studies, indicating that ISS are still a small fraction of the running clinical studies. IIS needs to be encouraged and supported in order to improve evidence-based decision-making and consequently bring maximum public health benefits.
The development of an IIS starts from a clinical re-search question. Indeed, physicians while providing medical care for patients often are confronted with re -levant clinical questions: which treatment is the best option for this disease or symptom? Is there any mar -ker of treatment response? Which symptom is predic-tor of a poor outcome? In order to test the clinical hy-pothesis, the adequate design (blinded/open, con-trolled/non controlled), treatment-arms, length of thera py, permitted concomitant therapy have to be de-fined at an early phase of protocol development. The outcome measures for accessing the primary (and secon dary) endpoint have to be carefully chosen to en-sure validity of results. Finally, regulatory aspects must be taken into account, and approvals of the National regulatory authorities that guarantee the protection and confidentiality of patients data (Comissão Nacional de Protecção de Dados), ethic issues (Comissão Ética para
1. Rheumatology Department, Hospital de Santa Maria, Lisbon Medical and Academic Centre, Lisboa, Portugal
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days, each subject will receive the assigned treatment for 6 months. Study visits are performed at baseline, week 4, week 12 and week 24. After the end of treat-ment, each subject will be followed for safety moni-toring and sustained efficacy assessment for 60 days. Data to assess disease activity (dactylitis, enthesitis, psoriasis, nail, peripheral and axial disease), functio -nality, health status (SF-36), quality of life (QoL), Der-matology Life Quality Index (DLQI) and adverse events are collected; peripheral blood samples are also collected. Magnetic resonance imaging (MRI) of the wrists and hands or the feet and ankle are performed according to a pre-determined protocol at baseline and week 24 depending on dactylitis location. If both, hand and feet fingers, are involved the most severely affected area, will be selected. GO-DACT primary endpoint is changes from baseline of the Dactylitis Seve -rity Score (DSS) at 24 weeks. Secondary efficacy end-points include: (1) Changes from baseline of dactyli-tis MRI score at week 24; (2) Changes from baseline of the LEI and SPARCC scores at 12 and 24 weeks; (3) Changes from baseline in 68 tender and 66 swollen joint counts at 12 and 24 weeks; (4) Changes from baseline of Bath Ankylosing Spondylitis Disease Acti -vity Index (BASDAI) and Ankylosing Spondylitis (AS) Disease Activity Score (ASDAS) at 12 and 24 weeks, in patients with axial involvement; (5) Proportion of pa-tients achieving Psoriasis Area and Severity Index (PASI) 50, 75 and 90 response at 12 and 24 weeks; (6) Changes from baseline in target Nail Psoriasis Severi-ty Index (target NAPSI) score, at week 12 and 24; (7) Changes from baseline in functional indexes Health Assessment Questionnaire Disability Index (HAQ) and Bath Ankylosing Spondylitis Functional Index (BASFI) at 12 and 24 weeks (for complete description of stu -dy design and endpoints see: Clinicaltrials.gov: NCT02065713).
“Biomarkers identification of anti-TNF aagent’s ef-ficacy in Ankylosing Spondylitis (AS) patients using a transcriptome analysis and mass spectrometry” is an ongoing prospective, single-arm, open-label, multi-centre IIS, designed to identify new candidate genes and proteins that are differentially expressed in res -ponders vsnon-responders to anti-TNF therapy.
Patients with AS according to SPR guidelines (1984 modified New York Criteria, but allowing the use of MRI as imaging criteria for sacroiliitis)4from seven Por-tuguese Hospitals, in whom anti-TNF therapy is indi-cated according to the Portuguese recommendations for the use of biological therapies4are included and
re-ceive adalimumab every other week, during a follow--up period of 14 weeks. Study visits are performed at baseline, 3-5 days, week 2 and week 14. Data related with disease activity, functionality, metrology, quality of life (QoL), adverse events are collected as well pe-ripheral blood samples. MRI of the entire rachis and SI joints is performed before baseline and after week 14, according to a predetermined protocol. At week 14 the whole group is divided in responders and nonres -ponders according to ASAS 20 criteria. The signature profiles between these 2 groups will be analysed. The study main aim is to identify biomarkers (gene and/or proteins) predicting efficacy to anti-TNF therapy, as defined by the ASAS 20 response-criteria. Secondary aims include: (1) identification of biomarkers (gene and/or proteins) predicting efficacy to antiTNF the -rapy according to the ASDAS response-criteria; (2) Bone and muscle MRI-changes under TNF therapy; and (3) QoL changes under TNF therapy. For addi-tional information related with the study protocol see ClinicalTrials.gov: NCT02492217.
ViscOA is an ongoing randomized double-blind placebo-controlled IIS designed to test the hypothesis that Intra-Articular Hyaluronic Acid (IAHA) is supe rior to placebo in slowing structural progression and on long-term symptomatic effect in primary knee Os-teoarthritis (KOA).
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ratory outcomes, including ultrasonography measure-ments and serum biomarkers, in KOA-assessment will be tested (for complete description of study design and endpoints see: Clinicaltrials.gov: NCT02280538).
The Portuguese Society of Rheumatology is com-mitted to support well-designed IITs that will improve rheumatology patient’s care. Such IITs do serve to add to the body of generalizable evidence and advance in rheumatology. IITs are a unique opportunity to con-tribute to clinical development and research.
coRRespondence to Elsa Vieira-Sousa
Rheumatology Research Unit, Instituto de Medicina Molecular Av. Prof. Egas Moniz
1649-028 Lisboa Portugal
E-mail: elsa-sousa@hotmail.com
RefeRences
1. http://www.infarmed.pt/portal/page/portal/INFARMED/DISPOSITIVOS_MEDICOS/INVESTIGACAO_CLINICA_AVALIA - CAO_FUNCIONAL/INFORMACAO_DIRIGIDA_FABRI-CANTES_INVESTIGACAO_CLINICA_DM. Date accessed: July 18 2016.
2. Evans I, Thornton H, Chalmers I (2010). Testing treatments: better research for better healthcare. London: Pinter and Mar-tin. Download text free at: www.jameslindlibrary.org/test-ingtreatments.html
3. Taylor W, Gladman D, Helliwell P, et al. Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum 2006. 54(8): 2665-2673. 4. Machado P, Bernardo A, Cravo AR, et al. Portuguese Society of
Rheumatology. Portuguese recommendations for the use of bi-ological therapies in patients with axial spondyloarthritis—De-cember 2011 update. Acta Reumatol Port 2012;37(1):40-47. 5. Altman R, Asch E, Bloch D et al. Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. Arthri-tis Rheum 1986;29(8):1039-1049.
